Pathologic Features of Down Syndrome Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Report From the Children's Oncology Group Protocol AAML0431.

CONTEXT.­: Detailed diagnostic features of acute myeloid leukemia in Down syndrome are lacking, leading to potential misdiagnoses as standard acute myeloid leukemia occurring in patients with Down syndrome. OBJECTIVE.­: To evaluate diagnostic features of acute myeloid leukemia and myelodysplastic syndrome in patients with Down syndrome. DESIGN.­: Diagnostic bone marrow samples from 163 patients enrolled in the Children's Oncology Group study AAML0431 were evaluated by using central morphologic review and institutional immunophenotyping. Results were compared to overall survival, event-free survival, GATA1 mutation status, cytogenetics, and minimal residual disease results. RESULTS.­: Sixty myelodysplastic syndrome and 103 acute myeloid leukemia samples were reviewed. Both had distinctive features compared to those of patients without Down syndrome. They showed megakaryocytic and erythroid but little myeloid dysplasia, and marked megakaryocytic hyperplasia with unusual megakaryocyte morphology. In acute myeloid leukemia cases, megakaryoblastic differentiation of blasts was most common (54 of 103, 52%); other cases showed erythroblastic (11 of 103, 11%), mixed erythroid/megakaryoblastic (20 of 103, 19%), or no differentiation (10 of 103, 10%). Myelodysplastic syndrome and acute myeloid leukemia cases had similar event-free survival and overall survival. Leukemic subgroups showed interesting, but not statistically significant, trends for survival and minimal residual disease. Cases with institutional diagnoses of French American British M1-5 morphology showed typical features of Down syndrome disease, with survival approaching that of other cases. CONCLUSIONS.­: Myelodysplastic syndrome and acute myeloid leukemia in Down syndrome display features that allow discrimination from standard cases of disease. These distinctions are important for treatment decisions, and for understanding disease pathogenesis. We propose specific diagnostic criteria for Down syndrome-related subtypes of acute myeloid leukemia and myelodysplastic syndrome.

Remodeling of Rectal Innervation After Pullthrough Surgery for Hirschsprung Disease: Relevance to Criteria for the Determination of Retained Transition Zone.

BACKGROUND: After pullthrough surgery for Hirschsprung disease (HSCR), Glut1-positive submucosal nerve hypertrophy is used to diagnose retained transition zone in the neorectum. We hypothesized that pelvic nerves, severed during pullthrough surgery, sprout into the neorectum to mimic transition zone. METHODS: The density (nerves/100x field) and maximum diameter of Glut1-positive submucosal nerves were measured in biopsies and redo resections from 20 patients with post-pullthrough obstructive symptoms. Their original and/or redo resections excluded unequivocal features of transition zone (myenteric hypoganglionosis or partial circumferential aganglionosis) in 17. Postoperative values were compared with control data from 28 cadaveric and 6 surgical non-HSCR specimens, and 14 primary HSCR resections. When possible, nerves were tracked from attached native pelvic soft tissue or aganglionic rectal cuff into the pulled-through colon. RESULTS: Glut1-positive submucosal nerves were not present in the 11 colons of non-HSCR infants less than 1 year of age, except sparsely in the rectum. In 17 older non-HSCR controls, occasional Glut1-positive nerves were observed in prerectal colon and were larger and more numerous in the rectum. In redo resections, Glut1-positive submucosal innervation in post-pullthrough specimens did not differ significantly from age-appropriate non-HSCR rectal controls and pelvic Glut1-positive nerves were never observed to penetrate the pulled-through colon. However, the density and caliber of Glut1-positive nerves in the neorectums were significantly greater than expected based on the prerectal location from which the pulled-through bowel originated. CONCLUSIONS: Submucosal innervation in post-pullthrough specimens does not support the hypothesis that native pelvic nerves innervate the neorectum, but suggests remodeling occurs to establish the age-appropriate density and caliber of rectal Glut1-positive innervation. The latter should not be interpreted as transition zone pullthrough in a rectal biopsy from a previously done pullthrough.

Clear cell renal cell carcinoma with intratumoral and nodal extramedullary megakaryopoiesis: a potential diagnostic pitfall.

Clear cell renal cell carcinoma is occasionally associated with erythrocytosis, hypothesized to result from tumoral production of erythropoietin. Rarely, intratumoral erythropoiesis has been identified, although intratumoral megakaryopoiesis has not, to our knowledge, been previously described. We report the case of an 81-year-old man with myelofibrosis who underwent resection of a 9.8-cm clear cell renal cell carcinoma. Numerous megakaryocytes were present within the renal cell carcinoma; regional lymph nodes; and, to a lesser extent, the nonneoplastic kidney, glomeruli, and renal hilar soft tissue, in some areas associated with trilineage hematopoiesis. Immunohistochemistry verified the megakaryocytic lineage of the atypical cells (CD61, CD42b, and von Willebrand factor +; cytokeratin -). Intratumoral extramedullary megakaryopoiesis is a novel finding in clear cell renal cell carcinoma with potential to mimic high-grade carcinoma and involvement of lymph nodes. Careful attention to morphology, presence of other hematopoietic elements, and immunoprofile can facilitate recognition of this rare phenomenon.

The coinheritance of beta- and alpha- thalassemia: a review of one patient and her family.

The diagnosis and management of alpha-thalassemia may be complicated by the variability of the phenotype, which is due to the interaction of coinherited alpha-thalassemia and the variable severity of beta-thalassemia mutations. A well-documented case of complex beta- and alpha-thalassemia coinheritance is described. Laboratory and clinical data for the patient and her family are reviewed. The patient is an asymptomatic girl, one of identical twins. She presented at 1 month of age for follow-up of an abnormal newborn-screening result (hemoglobin F only), which initially suggested homozygosity for beta-thalassemia. Extensive studies on the patient and family revealed that she had coinherited alpha-thalassemia traits and homozygous beta-thalassemia. This case demonstrates the interaction of coinherited alpha- and beta-thalassemia with the resultant amelioration of the clinical phenotype. It also highlights the importance of family studies and close follow-up in diagnosing complex hemoglobinopathies.

Desmopressin responsiveness in children with Ehlers-Danlos syndrome associated bleeding symptoms.

Ehlers-Danlos Syndrome (EDS) is caused by heritable collagen defects and may be associated with bleeding symptoms. Desmopressin has been described in case reports to decrease bleeding times in these patients. This study sought to assess bleeding time responsiveness to desmopressin therapy in a cohort of children with EDS-associated bleeding manifestations. A retrospective chart review of children with EDS referred for bleeding symptoms was utilized. Twenty-six children were included; 19 (73%) had a desmopressin challenge. The mean bleeding time was 11.26 (+/-4.39) min, decreasing to 5.95 (+/-2.41) min with treatment (P < 0.01). Desmopressin normalizes bleeding times in children with EDS.